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This section highlights the pathophysiologic complexity of sickle cell disease (SCD), the prototype of single-gene molecular disorders. James Herrick published the first clinical report of SCD in 1910. However, many decades passed before Linus Pauling established SCD as the first human monogenic disorder, with an autosomal recessive inheritance pattern, in 1949. This seminal work laid the foundation for the explosion of knowledge in human molecular genetics. Over the past few decades, the pathophysiology of SCD has been explored and clarified in many aspects, but other aspects still present uncertainties and lack of detail. The molecular mechanisms of the process leading to polymerization of hemoglobin S (HbS) and sickling have been elucidated in extreme detail, and this knowledge has been critical in rationalizing the beneficial effects of several of the novel therapies developed or under development for the disease. It has also become clear that a unique feature of SCD is the pathologic involvement of multiple organs most often as a consequence of vascular/inflammatory or ischemia-reperfusion complications of the disease. The interactions of sickle cells with the endothelium and the inflammatory response associated with the disease have been examined in a variety of experimental systems, with SCD emerging as a unique model of ischemia-reperfusion (I/R) disorders. These studies have been facilitated by the development of transgenic mouse models for SCD, which recapitulate disease pathophysiology and provide a model to test therapeutic interventions.

SCD is caused by homozygous mutations at the sixth codon of the β-globin gene in the β-globin cluster (HBB) on chromosome 11 (Figure I-1A), resulting in the production of the single aa hemoglobin variant, β6-Glu→Val (βS-globin). In the HBB cluster, the 5 functional globin genes, including ε-Gγ-Aγ-δ-β, are arranged 5′ to 3′ along the chromosome in the order of their developmental expression. The prevalence of SCD is about 1 in 365 African Americans and about 1 in 16,300 Hispanic Americans; in addition, about 1 in 13 African Americans are sickle cell trait carriers. In the United States, approximately 2000 babies are born annually with a major hemoglobinopathy and 100,000 individuals are affected; however, the exact number of people living with SCD is unknown. Although the molecular nature of SCD is relatively simple, its distribution in affected populations is more complex. Recent whole-genome–based haplotype analysis of individuals with sickle trait in the African Genome Variation Project identified a potential single origin of the βS-globin allele, approximately 7300 years ago. From its point of origin, the βS-globin gene expanded due to a selective advantage of healthy carriers of SCD providing protection against malaria infections.


Basic mechanisms of sickle cell disease (SCD). Shown is a summary of the mechanisms driving the clinical complications of SCD discussed in this overview. Based on current evidence, the pathophysiology of SCD is considered to be a vicious cycle of 4 major downstream processes: (A) hemoglobin S polymerization, (...

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